9-27547315-G-T

Variant names:

• chr9-27547315-G-T
• rs3739526
• NM_018325.5:c.*921C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018325.5(C9orf72):​c.*921C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,542 control chromosomes in the GnomAD database, including 3,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3013 hom., cov: 32)
  • Exomes 𝑓: 0.22 (10 hom.)
• Consequence: C9orf72 NM_018325.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.840
• Publications: 13 publications found

Genes affected

C9orf72 (HGNC:28337): (C9orf72-SMCR8 complex subunit) The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]

C9orf72 Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• progressive myoclonus epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-27547315-G-T is Benign according to our data. Variant chr9-27547315-G-T is described in ClinVar as Benign. ClinVar VariationId is 366490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018325.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	NM_018325.5	MANE Select	c.*921C>A		3_prime_UTR	Exon 11 of 11	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.*921C>A		3_prime_UTR	Exon 11 of 11	NP_001242983.1	Q96LT7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	ENST00000380003.8	TSL:1 MANE Select	c.*921C>A		3_prime_UTR	Exon 11 of 11	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.*921C>A		3_prime_UTR	Exon 11 of 11	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.*921C>A		3_prime_UTR	Exon 12 of 12	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28858 AN: 151992 Hom.: 3004 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.194

GnomAD4 exome AF: 0.220 AC: 95 AN: 432 Hom.: 10 Cov.: 0 AF XY: 0.229 AC XY: 59 AN XY: 258

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.223 AC: 95 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.190 AC: 28881 AN: 152110 Hom.: 3013 Cov.: 32 AF XY: 0.194 AC XY: 14428 AN XY: 74348

African (AFR) AF: 0.118 AC: 4879 AN: 41512

American (AMR) AF: 0.253 AC: 3857 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 499 AN: 3466

East Asian (EAS) AF: 0.300 AC: 1549 AN: 5168

South Asian (SAS) AF: 0.260 AC: 1256 AN: 4826

European-Finnish (FIN) AF: 0.239 AC: 2524 AN: 10560

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13637 AN: 67988

Other (OTH) AF: 0.197 AC: 416 AN: 2114

Alfa AF: 0.199 Hom.: 4570

Bravo AF: 0.191

Asia WGS AF: 0.279 AC: 971 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.3
DANN	Benign	0.59
PhyloP100		0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3739526; hg19: chr9-27547313; COSMIC: COSV66163288; COSMIC: COSV66163288;